ADJUST DOSE: Amiodarone may increase serum procainamide plasma concentrations by 55% and NAPA concentrations by 33% and increase its clearance. The mechanism is inhibition of CYP450 hepatic metabolism and renal clearance of procainamide. The risk of additive effects such as hypotension, QT interval prolongation, torsade de pointes and other arrhythmias is increased with concurrent therapy.

MANAGEMENT: If this combination cannot be avoided, a reduction in the procainamide dosage by one-third is recommended. Patients should be closely monitored for increased procainamide and NAPA levels, hypotension and new arrhythmias and be advised to report symptoms such as syncope, palpitations, nausea, or irregular heartbeats.

ADJUST DOSE: Amiodarone may markedly increase serum flecainide concentrations, probably by inhibiting CYP450 hepatic metabolism. One case of torsades de pointes has been reported. This interaction has a rapid onset but may take several weeks to maximally develop.

MANAGEMENT: A 30% to 50% reduction in flecainide dosage is recommended for patients receiving amiodarone. Flecainide plasma levels should be monitored and patients should be closely observed for clinical response and signs of flecainide toxicity (nausea, vomiting, new or worsened arrhythmias) for several weeks.

ADJUST DOSE: Coadministration of amiodarone and disopyramide may increase the risk of arrhythmias including torsade de pointes due to their combined depressant effects on cardiac conduction, which could lead to excessive prolongation of the QT interval of the electrocardiogram. In addition, amiodarone may decrease the clearance of disopyramide by inhibiting its metabolism via CYP450 3A4, although pharmacokinetic data are lacking. Despite the potential toxicities, the combination has been use therapeutically in the treatment of certain ventricular arrhythmias.

MANAGEMENT: In general, the concurrent use of amiodarone with other antiarrhythmic agents should be reserved for patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent or to amiodarone alone. If adding or transferring to amiodarone, the dosages of previously administered agents should be reduced by 30% to 50% several days after the addition of amiodarone, when onset of arrhythmia suppression should occur. The continued need for other antiarrhythmic agents should be evaluated after the effects of amiodarone have been established, and discontinuation should generally be attempted. If the combination is continued, patients should be monitored for adverse effects including conduction disturbances and exacerbation of tachyarrhythmias. In amiodarone-treated patients who require additional antiarrhythmic agents, the initial dosage of such agents should be approximately one-half the usual recommended dosage.

ADJUST DOSE: Coadministration of amiodarone and mexiletine has been associated with an isolated case of torsade de pointes. The mechanism of interaction is unknown, as mexiletine has not been shown to prolong the QT interval of the electrocardiogram. In fact, mexiletine has been used in the treatment of torsade de pointes. A study of patients with supraventricular tachyarrhythmias treated with a combination of amiodarone and mexiletine or mexiletine alone found no evidence of a pharmacokinetic interaction. Some investigators have also reported on the safe and effective use of the combination.

MANAGEMENT: In general, the concurrent use of amiodarone with other antiarrhythmic agents should be reserved for patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent or to amiodarone alone. If adding or transferring to amiodarone, the dosages of previously administered agents should be reduced by 30% to 50% several days after the addition of amiodarone, when onset of arrhythmia suppression should occur. The continued need for other antiarrhythmic agents should be evaluated after the effects of amiodarone have been established, and discontinuation should generally be attempted. If the combination is continued, patients should be monitored for adverse effects including conduction disturbances and exacerbation of tachyarrhythmias. In amiodarone-treated patients who require additional antiarrhythmic agents, the initial dosage of such agents should be approximately one-half the usual recommended dosage.

ADJUST DOSE: Coadministration with amiodarone may increase serum digoxin concentrations by up to 100%, frequently resulting in clinical toxicity. In children, this percentage may be even higher. Amiodarone has been suggested to increase intestinal transit time, reduce renal clearance and volume of distribution, displace digoxin from protein binding sites, as well as induce hypothyroidism, all of which may contribute to increased serum digoxin levels. In addition, both drugs may have additive bradycardic effects. Torsade de pointes cardiac arrhythmia has been reported. The interaction also has occurred with digitoxin.

MANAGEMENT: The need for continued digitalis therapy should be evaluated if amiodarone is prescribed to patients treated with digitalis. Empirical reduction of digitalis dosage by one-third to one-half should be considered in patients who require concomitant treatment with these drugs. Serum digitalis levels should be closely monitored and patients observed for clinical evidence of toxicity. Patients should be advised to seek medical attention if they experience signs of digitalis toxicity such as nausea, anorexia, visual disturbances, slow pulse, or irregular heartbeats.

ADJUST DOSE: Coadministration with drugs that are inhibitors of CYP450 1A2 may increase the plasma concentrations of rasagiline, which is a substrate of the isoenzyme. In 12 healthy volunteers, coadministration with ciprofloxacin (500 mg twice a day) increased the systemic exposure (AUC) of rasagiline (2 mg once a day) by 83%, with no change in elimination half-life.

MANAGEMENT: Patients treated concomitantly with potent inhibitors of CYP450 1A2 such as ciprofloxacin or fluvoxamine should use rasagiline 0.5 mg/day. Patients receiving other CYP450 1A2 inhibitors should initiate therapy at the lower dosage, then increase gradually as necessary.

ADJUST DOSE: Coadministration with drugs that are inhibitors of CYP450 3A4 may increase the plasma concentrations of tolterodine, which is partially metabolized by the isoenzyme. The possibility of prolonged and/or increased pharmacologic effects of tolterodine should be considered. Although tolterodine is primarily metabolized by CYP450 2D6, there is some evidence that CYP450 3A4 may play a minor role, thus any alteration in its activity levels could conceivably affect the metabolism of tolterodine. The clinical significance of this interaction is yet unknown but may be greater in patients who are CYP450 2D6-deficient, or so-called poor metabolizers of CYP450 2D6 (approximately 7% of Caucasians and less than 2% of Asians and individuals of African descent).

MANAGEMENT: The manufacturer recommends a maximum tolterodine dosage of 1 mg twice daily in patients receiving concomitant CYP450 3A4 inhibitors. Close clinical and laboratory monitoring is advised whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy. Patients should be advised to notify their physician if they experience an irregular heartbeat, severe blurry vision, difficulty urinating, dry mouth, headache, drowsiness, dizziness, or GI upset.

ADJUST DOSE: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of eplerenone, which is primarily metabolized by the isoenzyme. In pharmacokinetic studies, administration of eplerenone (100 mg single dose) with the potent inhibitor ketoconazole (200 mg twice a day) resulted in a 1.7-fold increase in eplerenone peak plasma concentration (Cmax) and a 5.4-fold increase in systemic exposure (AUC), while administration with other 3A4 inhibitors (erythromycin 500 mg twice daily; verapamil 240 mg once daily; saquinavir 1200 mg three times daily; fluconazole 200 mg once daily) resulted in increases in eplerenone Cmax ranging from 1.4- to 1.6-fold and AUC from 2.0 to 2.9-fold.

MANAGEMENT: Eplerenone should not be used with potent inhibitors of CYP450 3A4 (e.g., itraconazole, ketoconazole, nefazodone, delavirdine, ketolide and certain macrolide antibiotics, most protease inhibitors) and should be used cautiously with other inhibitors of the isoenzyme. The initial dosage of eplerenone should be reduced to 25 mg once daily during concomitant therapy with moderate inhibitors and titrated slowly based on therapeutic response.

ADJUST DOSE: The use of amiodarone with higher dosages of simvastatin or lovastatin may be associated with an increased risk of myopathy. In an ongoing clinical trial, myopathy has been reported in 6% of patients receiving simvastatin 80 mg and amiodarone. There is also a reported case of rhabdomyolysis in a patient who received simvastatin 40 mg with amiodarone for 2 weeks. The proposed mechanism is amiodarone inhibition of simvastatin metabolism via intestinal and hepatic CYP450 3A4, resulting in significantly enhanced bioavailability and reduced clearance of simvastatin. Although not studied, the interaction is also expected to occur with lovastatin due to its similar metabolic profile to simvastatin. In general, the risk of myopathy associated with the statin class of drugs is thought to be dose-related and increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Myopathy manifested as muscle pain and/or weakness associated with grossly elevated creatine kinase exceeding ten times the upper limit of normal has been reported occasionally. Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death.

MANAGEMENT: Simvastatin dosage should generally not exceed 20 mg daily and lovastatin dosage not exceed 40 mg daily when used in combination with amiodarone unless the clinical benefit is anticipated to outweigh the increased risk of myopathy. Fluvastatin, pravastatin, and rosuvastatin are probably safer alternatives in patients receiving amiodarone, since they are not metabolized by CYP450 3A4. All patients treated with HMG-CoA reductase inhibitors should be advised to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed.

Amiodarone may increase the pharmacologic effect of benzodiazepines by its adrenergic blocking effects. Data are available for diazepam. Management consists of monitoring the patient's mental status during coadministration.

Coadministration with drugs that are inhibitors of the CYP450 3A4 isoenzyme may increase the plasma concentrations and pharmacologic effects of modafinil, which is partially metabolized by the isoenzyme. Conversely, the plasma levels of some of these inhibitors may decrease, since many of them are also substrates of CYP450 3A4, and modafinil has been shown to be a modest inducer of CYP450 3A4 in vitro. The clinical significance of this potential interaction is unknown. Clinical monitoring for altered effects of both modafinil and the CYP450 3A4 inhibitor may be appropriate following addition or withdrawal of one or the other drug. Dose adjustments may be required if an interaction is suspected.

Coadministration with inhibitors of CYP450 2D6 and/or 3A4 may increase the plasma concentrations of donepezil, which is primarily metabolized by these isoenzymes. In a 7-day crossover study in 18 healthy volunteers, the potent CYP450 3A4 inhibitor ketoconazole (200 mg once daily) increased the mean peak plasma concentration (Cmax) and systemic exposure (AUC) of donepezil (5 mg once daily) by approximately 36% each. The clinical relevance of these increases is unknown.

Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of retapamulin, which is primarily metabolized by the isoenzyme. In healthy adult males, coadministration of the potent CYP450 3A4 inhibitor ketoconazole (200 mg orally twice a day) increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of retapamulin by 81% following topical application of retapamulin ointment 1% on abraded skin. However, dosage adjustments are not necessary due to the low systemic exposure to retapamulin following topical application.

Combined use of amiodarone and dextromethorphan may cause increased serum concentrations of dextromethorphan. Amiodarone inhibits hepatic cytochrome P450 (CYP2D6) and interferes with the metabolism of dextromethorphan. Caution should be exercised if these drugs must be used together, and patients should be monitored for signs of dextromethorphan toxicity (e.g., confusion, agitation).

CONTRAINDICATED: Amiodarone, benoquin, chloroquine, and gentamicin may have the potential to inhibit intracellular alpha-galactosidase activity, thereby reducing the pharmacologic effects of agalsidase alfa and agalsidase beta. Clinical data have not been reported.

MANAGEMENT: Agalsidase should not be coadministered with amiodarone, benoquin, chloroquine, or gentamicin.

CONTRAINDICATED: Cisapride can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction.

MANAGEMENT: The concurrent use of cisapride with other medications that can prolong the QT interval is considered contraindicated.

CONTRAINDICATED: Coadministration with indinavir may significantly increase the plasma concentrations of amiodarone. The proposed mechanism is indinavir inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of amiodarone. Although clinical data are lacking, the interaction could conceivably lead to serious and/or life-threatening reactions including QT interval prolongation and ventricular arrhythmias such as ventricular tachycardia and torsade de pointes.

MANAGEMENT: The use of indinavir with amiodarone is considered contraindicated by the manufacturer.

CONTRAINDICATED: Coadministration with nelfinavir may significantly increase the plasma concentrations of amiodarone and quinidine. The proposed mechanism is nelfinavir inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of these antiarrhythmic agents. Although clinical data are lacking, the interaction could conceivably lead to serious and/or life-threatening reactions including QT interval prolongation and ventricular arrhythmias such as ventricular tachycardia and torsade de pointes.

MANAGEMENT: The use of nelfinavir with amiodarone or quinidine is considered contraindicated.

CONTRAINDICATED: Coadministration with ritonavir may significantly increase the plasma concentrations of some antiarrhythmic agents such as amiodarone, bepridil, flecainide, propafenone, and quinidine. The proposed mechanism is ritonavir inhibition of CYP450 3A4 and/or 2D6, the isoenzymes responsible for the metabolic clearance of these agents. Although clinical data are lacking, the interaction could conceivably lead to serious and/or life-threatening reactions including QT interval prolongation and ventricular arrhythmias such as ventricular tachycardia and torsade de pointes.

MANAGEMENT: The use of ritonavir with amiodarone, bepridil, flecainide, propafenone, or quinidine is considered contraindicated.

CONTRAINDICATED: Dofetilide should not be used with Class I or other Class III antiarrhythmic agents due to the potential for additive effects on myocardial refractoriness. Many of these agents, including dofetilide, can also cause prolongation of the QT interval, thus concomitant use may increase the risk of ventricular arrhythmias such as ventricular tachycardia and torsade de pointes.

MANAGEMENT: Class I (e.g., disopyramide, quinidine, procainamide) and class III (e.g., amiodarone, ibutilide, sotalol) antiarrhythmic agents should be withheld for at least 3 half-lives before administering dofetilide. In the case of amiodarone with its unpredictable pharmacokinetics, dofetilide should not be initiated until serum amiodarone levels are below 0.3 mcg/mL or amiodarone has been withdrawn for at least three months.

CONTRAINDICATED: Grepafloxacin can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction.

MANAGEMENT: The concurrent use of grepafloxacin with other medications that can prolong the QT interval is considered contraindicated.

CONTRAINDICATED: Halofantrine can cause dose-related prolongation of the QT interval at recommended therapeutic doses. QTc interval prolongation and death have been reported during combination use of halofantrine and mefloquine. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction.

MANAGEMENT: The concurrent use of halofantrine with other medications that can prolong the QT interval is considered contraindicated. Halofantrine should also not be given to patients who have previously taken mefloquine. The manufacturer recommends performing an ECG before initiating halofantrine therapy and monitoring cardiac rhythm during and for 8 to 12 hours after completion of therapy.

CONTRAINDICATED: Mesoridazine can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. Mesoridazine overdosage has been associated with ventricular arrhythmias and death.

MANAGEMENT: The concurrent use of mesoridazine with other medications that can prolong the QT interval is considered contraindicated.

CONTRAINDICATED: Pimozide can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction.

MANAGEMENT: The concurrent use of pimozide with other medications that can prolong the QT interval is considered contraindicated.

CONTRAINDICATED: Quinolones such as gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, and sparfloxacin may cause dose-related prolongation of the QT interval in some patients. Coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. Torsade de pointes have been reported in a few patients receiving sparfloxacin alone and with antiarrhythmic agents like amiodarone and disopyramide. There have also been isolated case reports of clinically significant interactions with sotalol, a class III antiarrhythmic agent, for both gatifloxacin and moxifloxacin. Levofloxacin, lomefloxacin, norfloxacin, and ofloxacin alone have been associated with extremely rare cases of torsade de pointes and ventricular tachycardia.

MANAGEMENT: Product labelings for some quinolones recommend avoiding concomitant therapy with class IA (e.g., disopyramide, quinidine, procainamide) and class III (e.g., amiodarone, dofetilide, ibutilide, sotalol) antiarrhythmic agents, as well as bepridil. Sparfloxacin is additionally contraindicated for use with any other medication that can prolong the QT interval such as cisapride, erythromycin, some antipsychotics, and tricyclic antidepressants.

CONTRAINDICATED: Ranolazine can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. With repeat dosing, the mean effect of ranolazine (1000 mg twice daily) on QTc at Tmax is about 6 msec. However, in 5% of the population, the prolongation of QTc is 15 msec. The relationship between ranolazine plasma level and QTc remains linear over a concentration range up to 4-fold greater than the concentrations produced by a dosage of 1000 mg twice a day, and this relationship is not significantly affected by age, weight, gender, race, heart rate, congestive heart failure NYHA class, or diabetes.

MANAGEMENT: The concurrent use of ranolazine with other medications that can prolong the QT interval is considered contraindicated.

CONTRAINDICATED: Thioridazine can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. Thioridazine treatment alone has been associated with several reported cases of torsade de pointes and sudden death.

MANAGEMENT: The concurrent use of thioridazine with other medications that can prolong the QT interval is considered contraindicated.

CONTRAINDICATED: Ziprasidone can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction.

MANAGEMENT: The concurrent use of ziprasidone with other medications that can prolong the QT interval is considered contraindicated.

MANAGEMENT: Coadministration of amiodarone with medications that can cause potassium and/or magnesium disturbances should generally be avoided. Serum electrolytes should be evaluated and any abnormalities corrected prior to initiating therapy with amiodarone. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsades de pointes such as dizziness, palpitations, or syncope.

GENERALLY AVOID: Arsenic trioxide can cause QT interval prolongation and complete atrioventricular block. Theoretically, coadministration with other agents that can prolong the QT interval may increase the risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. During clinical studies involving 40 patients receiving arsenic trioxide for acute promyelocytic leukemia, 16 of them (40%) had at least one ECG tracing with a QTc interval greater than 500 msec. Prolongation of QTc was observed between 1 and 5 weeks after arsenic trioxide infusion and returned towards baseline by the end of 8 weeks. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: If possible, medications that are known to prolong the QT interval should be discontinued prior to initiating therapy with arsenic trioxide and withheld for at least several weeks after completion of therapy. Caution is advised if concomitant use cannot be avoided. Patients should have frequent ECGs and be monitored for arrhythmias when QT intervals are prolonged. An absolute QT interval exceeding 500 msec will require immediate action to correct concomitant risk factors, if any, as well as a thorough assessment of the need for continued therapy. Patients who develop syncope or arrhythmia should be hospitalized for clinical and laboratory monitoring. Arsenic trioxide should be temporarily discontinued until symptoms resolve, the QTc interval regresses to below 460 msec, and electrolyte abnormalities are corrected.

GENERALLY AVOID: Class IA (e.g., disopyramide, quinidine, procainamide) and class III (e.g., amiodarone, dofetilide, sotalol) antiarrhythmic agents can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: The concurrent use of class IA or class III antiarrhythmic agents with other medications that can prolong the QT interval should preferably be avoided unless benefits are anticipated to outweigh the risks. Caution and clinical monitoring are recommended if these agents are prescribed together, especially to patients with underlying risk factors. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsades de pointes such as dizziness, palpitations, or syncope.

GENERALLY AVOID: Coadministration with azole antifungal agents may significantly increase the plasma concentrations of amiodarone. The proposed mechanism is azole inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of amiodarone. The use of amiodarone has been associated with prolongation of the QT interval, thus elevated plasma levels of the drug may potentiate the risk of ventricular arrhythmias such as ventricular tachycardia and torsade de pointes as well as cardiac arrest and sudden death. Within the azole class, ketoconazole and itraconazole are considered potent inhibitors, while fluconazole is comparatively weak and generally causes clinically significant interactions with CYP450 3A4 substrates only at dosages of 200 mg/day or more.

MANAGEMENT: Given the potential for serious and life-threatening adverse cardiac events associated with increased plasma levels of amiodarone, concomitant use with azole antifungal agents should generally be avoided if possible. Otherwise, caution and close clinical monitoring are recommended, and patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope.

GENERALLY AVOID: Coadministration with inhibitors of CYP450 1A2 may significantly increase the plasma concentrations and pharmacologic effects of tizanidine, which is a substrate of the isoenzyme. In 10 healthy volunteers, pretreatment with the potent CYP450 1A2 inhibitor fluvoxamine (100 mg orally once daily for 4 days) increased the peak plasma concentration (Cmax) and systemic exposure (AUC) of tizanidine (4 mg single oral dose) by an average of 12- and 33-fold, respectively, compared to placebo. The mean elimination half-life of tizanidine was prolonged from 1.5 to 4.3 hours by fluvoxamine. Similarly, pretreatment with ciprofloxacin (500 mg orally twice daily for 3 days) increased the Cmax and AUC of tizanidine (4 mg single oral dose) by an average of 7- and 10-fold, respectively, compared to placebo. In addition, pharmacologic effects of tizanidine as measured by changes in blood pressure, heart rate, performance testing, subjective drug effect, and drowsiness were significantly greater with fluvoxamine and ciprofloxacin compared to placebo. The interaction was also suspected in a case report of a 70-year-old patient who developed low heart rate, low body temperature, dry mouth, and anuresis during tizanidine administration two weeks after initiating fluvoxamine. A retrospective review of patient medical records at the hospital revealed a significantly higher incidence of tizanidine-related adverse effects in patients treated concomitantly with fluvoxamine than that reported for tizanidine alone in the product labeling (26.1% vs. 5.3%), and those who experienced adverse effects were older and received higher dosages of both drugs than those who did not have adverse effects with the combination. Another CYP450 1A2 inhibitor, rofecoxib, has also been reported to potentiate the adverse effects of tizanidine. There have been postmarketing reports of adverse events mostly involving the nervous system (e.g., hallucinations, psychosis, somnolence, hypotonia) and cardiovascular system (e.g., hypotension, tachycardia, bradycardia) during concomitant use of tizanidine and rofecoxib. In all cases, adverse events resolved following discontinuation of one or both drugs. Rechallenges were not performed.

MANAGEMENT: The use of tizanidine in combination with CYP450 1A2 inhibitors should generally be avoided. Caution is advised if concurrent use is clinically necessary. Dosage adjustments may be required in patients who experience excessive adverse effects of tizanidine such as drowsiness, dizziness, lightheadedness, hypotension, or bradycardia.

GENERALLY AVOID: Tacrolimus can cause dose-related prolongation of the QT interval. Theoretically, coadministration with class IA (e.g., disopyramide, quinidine, procainamide) or class III (e.g., amiodarone, dofetilide, sotalol) antiarrhythmic agents may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. Pharmacokinetically, some of these agents (e.g., amiodarone, bepridil, disopyramide, dofetilide, quinidine) are also known to be substrates and/or inhibitors of CYP450 3A4 and may inhibit the metabolism of tacrolimus, which could lead to increased blood concentrations and toxicity.

MANAGEMENT: Tacrolimus should probably not be administered with class IA or class III antiarrhythmic agents unless benefits are anticipated to outweigh the risks. Caution and clinical monitoring are recommended if these agents are prescribed together. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope. In addition, tacrolimus blood levels and renal function should be checked frequently when given with known substrates and/or inhibitors of CYP450 3A4, and the dosage adjusted accordingly.

GENERALLY AVOID: Telithromycin has the potential to prolong the QT interval of the electrocardiogram in some patients. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction.

GENERALLY AVOID: Use of abarelix may cause prolongation of the QT interval in some patients. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. In a single, active-controlled, clinical study comparing abarelix to LHRH (luteinizing hormone releasing hormone) agonist plus nonsteroidal antiandrogen therapy, both therapies were found to prolong the mean Fridericia-corrected QT interval by more than 10 msec from baseline. In approximately 20% of patients in both groups, there were either changes from baseline QTc of greater than 30 msec or end-of-treatment QTc values exceeding 450 msec. Similar results were observed in two other Phase 3 studies with abarelix and the active-control treatments. It is unclear whether these changes were directly related to study drugs, to androgen deprivation therapy, or to other variables.

GENERALLY AVOID: Vardenafil has been reported to cause prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. In a study of the effect of vardenafil on QT interval in 59 healthy volunteers, therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produced similar increases in QTc interval as moxifloxacin 400 mg, the active control.

GENERALLY AVOID: Zalcitabine can cause peripheral neuropathy in up to one-third of patients with advanced HIV disease, and concurrent use of other agents that are also associated with this adverse effect can potentiate the risk. Zalcitabine-related peripheral neuropathy is a sensorimotor neuropathy characterized initially by numbness and burning dysesthesia involving the distal extremities. These symptoms may be followed by sharp shooting pains or severe continuous burning pain if the drug is not withdrawn, and progress to severe pain requiring narcotic analgesics. The neuropathy is potentially irreversible.

MANAGEMENT: Use of zalcitabine in combination with other drugs that have the potential to cause peripheral neuropathy should be avoided whenever possible. If concomitant use is necessary, careful monitoring for symptoms of neuropathy such as burning, tingling, pain, or numbness in the hands and feet is recommended, particularly in patients with a low CD4 cell count. Since the development of peripheral neuropathy appears to be dose-related, the recommended dosage of zalcitabine should not be exceeded. Patients should be advised to promptly discontinue zalcitabine therapy if neuropathy develops. Therapy may be reinstituted following resolution of neuropathy symptoms, but dosage should be reduced to one-half the initially recommended dosage. Zalcitabine should be permanently discontinued in patients who develop severe peripheral neuropathy during treatment.

MONITOR: A case report has suggested that amiodarone may increase the risk of methotrexate toxicity (particularly skin necrosis). The mechanism is unknown and causality could not be definitely determined.

MANAGEMENT: Patients receiving this combination should be monitored for signs of dermatologic reactions (e.g., ulceration, necrosis).

MONITOR: Additive effects of severe bradycardia, cardiac arrest, and ventricular fibrillation may occur in patients administered amiodarone and beta blockers. The mechanism may be related to additive slowing in AV conduction. In addition, amiodarone may inhibit the first pass hepatic metabolism of some beta blockers. However, a post hoc meta analysis suggests that the addition of amiodarone in patients in whom it is indicated, who are recovering from a recent myocardial infarction, and who are already receiving beta-blockers decreases the incidence of cardiac or arrhythmic death.

MONITOR: Amide-type local anesthetics may have additive cardiac effects (e.g., bradycardia, chest pain, heart block, arrhythmias, ECG abnormalities, cardiac arrest) with class III antiarrhythmic agents. Although specific trials studying the interaction have not been performed, a case report suggests additive depressive effects of amiodarone and lidocaine on the sinoatrial node. A 64-year-old man with sick sinus syndrome developed severe, symptomatic sinus bradycardia and sinoatrial arrest following local anesthesia with lidocaine while he was on amiodarone therapy. No other cause was identified.

MANAGEMENT: Patients treated with class III antiarrhythmic agents (e.g., amiodarone, dofetilide, ibutilide, sotalol) should be under close surveillance during administration of amide-type local anesthetics. ECG monitoring should be considered.

MANAGEMENT: Management consists of monitoring serum hydantoin concentrations and amiodarone effectiveness for several weeks after beginning therapy. Patients should be advised to notify their physician if they experience symptoms of toxicity (e.g., drowsiness, visual disturbances, change in mental status, seizures, nausea, or ataxia) or a worsening of their arrhythmia.

MONITOR: Amiodarone may decrease the hepatic metabolism of theophylline. Increased theophylline serum concentrations may result. Patients with chronic obstructive pulmonary disease, congestive heart failure, or cirrhosis may have slower theophylline clearance rates; therefore, they may be at greater risk of developing theophylline toxicity.

MANAGEMENT: If these drugs are given concurrently, close clinical and laboratory monitoring of response and tolerance is recommended. An interaction may not become apparent for several weeks. Patients should be advised to notify their physician if they experience any signs of theophylline toxicity including nausea, vomiting, diarrhea, headache, restlessness, insomnia, seizures, or a worsening of their arrhythmia. It may be necessary to reduce theophylline dosage.

MONITOR: Amiodarone serum concentrations may be increased during concomitant therapy with cimetidine and toxicity could result. The mechanism is not known but may involve inhibition of amiodarone hepatic metabolism or of uptake by hepatocytes. Given the long half-life of amiodarone, it may take several weeks for the full effect of the interaction to be realized.

MANAGEMENT: If amiodarone and cimetidine must be used concomitantly, monitoring of amiodarone serum concentrations is recommended.

MONITOR: Based on in vitro data, coadministration with oxcarbazepine may decrease the plasma concentrations of drugs that are substrates of the CYP450 3A4 and 3A5 isoenzymes. The mechanism is accelerated clearance due to induction of CYP450 3A activities by oxcarbazepine. In one study, a single dose of oxcarbazepine (600 mg) had no effect on the pharmacokinetics of felodipine, a CYP450 3A4 substrate, while repeated doses (450 mg twice a day) decreased the peak plasma concentration and area under the concentration-time curve of felodipine (10 mg once daily) by 34% and 28%, respectively. Likewise, in a single case study, cyclosporine trough concentrations decreased to subtherapeutic levels a little over 2 weeks after addition of oxcarbazepine in a renal transplant patient. These results indicate that enzymatic induction occurs after multiple doses.

MANAGEMENT: Caution is advised if oxcarbazepine must be used concurrently with medications that undergo metabolism by CYP450 3A4 and/or 3A5, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever oxcarbazepine is added to or withdrawn from therapy.

MONITOR: Based on in vitro inhibition data, coadministration with mifepristone may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by mifepristone.

MANAGEMENT: Caution is advised if mifepristone must be used concomitantly with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever mifepristone is added to or withdrawn from therapy. Because mifepristone is eliminated slowly from the body, drug interactions may be observed for a prolonged period.

MONITOR: Bortezomib can cause peripheral neuropathy, and concurrent use of other agents that are also associated with this adverse effect can potentiate the risk. Bortezomib treatment causes a peripheral neuropathy that is predominantly sensory, although cases of mixed sensori-motor neuropathy have also been reported. During clinical trials, 37% of the patients experienced treatment emergent neuropathy. Of these, more than 70% had previously been treated with neurotoxic agents and more than 80% of these patients had signs or symptoms of peripheral neuropathy at baseline. The incidence of grade 3 neuropathy (i.e., that which interferes with activities of daily life) was 5% in patients without baseline neuropathy.

MANAGEMENT: Caution is advised if bortezomib is used in combination with other neurotoxic agents. Patients should be monitored closely for symptoms of neuropathy such as visual disturbances or burning, tingling, or numbness in the hands and feet. Patients experiencing new or worsening peripheral neuropathy may require a change in the dosage and schedule of bortezomib in accordance with product labeling. Symptoms may improve or return to baseline in some patients upon discontinuation of bortezomib, although the complete time-course of this toxicity has not been fully characterized.

MANAGEMENT: A 30 to 50% reduction in quinidine dosage is recommended for patients receiving amiodarone. Patients should be closely monitored for signs of quinidine toxicity, and serum levels, electrolyte levels, and ECG should also be monitored. Patients should be advised to promptly report any early symptoms of toxicity including nausea, vomiting, diarrhea, tinnitus, hearing loss, visual disturbances, dizziness, headache, and confusion.

MONITOR CLOSELY: Amiodarone may increase the pharmacologic effects of warfarin by inhibiting CYP450 2C9 hepatic metabolism of S-warfarin. Similar effects may also occur with other oral anticoagulants, resulting in significant hypoprothrombinemia and bleeding. When amiodarone is added to an anticoagulant regimen, increased anticoagulant effects may become apparent within one to several weeks and may persist for months after the amiodarone is discontinued. The effects of this interaction are highly variable - while some patients are asymptomatic, serious and life-threatening bleeding complications have been reported in others. Patients who are poor CYP450 2C9 metabolizers may have a higher risk of bleeding and a faster onset of the interaction.

MANAGEMENT: An empiric 30% to 50% reduction in anticoagulant dosage has been recommended, in addition to frequent monitoring of the patient and the prothrombin time or International Normalized Ratio (INR). Patients should be advised to notify their physician promptly if they experience any signs of excessive anticoagulation such as unusual or prolonged bleeding, bruising, vomiting, change in stool or urine color, headache, dizziness, or weakness.

MONITOR CLOSELY: Coadministration with amprenavir or its prodrug, fosamprenavir, may significantly increase the plasma concentrations of amiodarone, systemic lidocaine, and quinidine. The proposed mechanism is amprenavir inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of these antiarrhythmic agents. The interaction has not been studied but could conceivably lead to serious and/or life-threatening reactions including cardiac arrhythmias and other toxicities.

MANAGEMENT: Caution is advised if amprenavir or fosamprenavir must be used with amiodarone, systemic lidocaine, or quinidine. Pharmacologic response and plasma antiarrhythmic drug levels should be monitored more closely whenever amprenavir or fosamprenavir is added to or withdrawn from therapy, and the antiarrhythmic dosage adjusted as necessary.

MONITOR CLOSELY: Coadministration with conivaptan may significantly increase the plasma concentrations of certain antiarrhythmic agents such as amiodarone, lidocaine, and quinidine. The mechanism is conivaptan inhibition of CYP450 3A4 metabolism. The interaction has not been specifically studied but could conceivably lead to serious and/or life-threatening reactions including cardiac arrhythmias and other toxicities. In pharmacokinetic studies with other drugs that are primarily metabolized by CYP450 3A4 such as midazolam, simvastatin, and amlodipine, conivaptan has increased systemic exposure (AUC) by 2- to 3-fold.

MANAGEMENT: Caution is advised if conivaptan must be used with antiarrhythmic agents that are primarily metabolized by CYP450 3A4 such as amiodarone, lidocaine, or quinidine. Pharmacologic response and plasma antiarrhythmic drug levels should be monitored more closely whenever conivaptan is added to or withdrawn from therapy, and the antiarrhythmic dosage adjusted as necessary.

MONITOR CLOSELY: Coadministration with inhibitors of CYP450 3A4 such as amiodarone may increase the plasma concentrations of fentanyl, which is metabolized by the isoenzyme. Increased fentanyl concentrations could conceivably increase or prolong adverse drug effects and may cause potentially fatal respiratory depression.

MONITOR CLOSELY: Amiodarone may increase the risk of cardiovascular complications during or after general anesthesia with fentanyl. The mechanism of interaction is unknown. Severe refractory vasodilatation, hypotension, bradycardia, myocardial depression, low cardiac output, increased pacemaker dependency, heart block, and other conduction defects have been reported during surgical procedures involving fentanyl. Treatment has included inotropic support and pressor agents, but fatality has occurred despite these measures. Causality has not been clearly determined due to the presence of other medications in reported cases as well as conflicting data in some studies. One study consisting of patients undergoing coronary artery bypass grafting or valvular surgery found no adverse hemodynamic effects of short-term amiodarone during fentanyl-isoflurane anesthesia.

MANAGEMENT: Patients receiving fentanyl in combination with CYP450 3A4 inhibitors such as amiodarone should be carefully monitored, and dosage adjustments made accordingly if necessary. Patients and/or their caregivers should be advised to seek medical attention if potential signs and symptoms of toxicity occur such as dizziness, confusion, fainting, extreme sedation, bradycardia, slow or difficult breathing, and shortness of breath. Patients treated with transdermal formulations of fentanyl should be cautioned that drug interactions and drug effects may be observed for a prolonged period beyond removal of the patch, as significant amounts of fentanyl are absorbed from the skin for 17 hours or more after the patch is removed. Patients receiving fentanyl-containing anesthesia should be closely monitored for hemodynamic instability and other cardiovascular complications, and appropriate measures taken as required.

MONITOR CLOSELY: Dolasetron can cause dose-related prolongation of the QT interval via its pharmacologically active metabolite, hydrodolasetron. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. In clinical trials, ECG interval prolongations usually returned to baseline within 6 to 8 hours after administration but lasted more than 24 hours in some patients. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Caution is recommended when dolasetron is administered concomitantly with drugs that prolong the QT interval (including cumulative high-dose anthracycline therapy), especially to patients with underlying risk factors. ECG monitoring may be appropriate in high-risk patients. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope.

MONITOR CLOSELY: Like other class III antiarrhythmic agents, amiodarone can cause dose-related QT interval prolongation. Coadministration with macrolides, which can also prolong the QT interval, may increase the risk of ventricular arrhythmias including ventricular tachycardia and torsade de pointes because of additive arrhythmogenic potential related to their effects on cardiac conduction. A case of QT interval prolongation and increased QT dispersion has been reported in a patient 3 days after oral azithromycin was added to a regimen that included oral amiodarone. The QTc interval increased from 510 ms to 660 ms and QT dispersion increased from 58 ms to 140 ms. The ECG returned to baseline values 4 days after the azithromycin was discontinued. Erythromycin, clarithromycin, and troleandomycin are also potent inhibitors of CYP450 3A4 and may significantly inhibit the metabolism of amiodarone, resulting in increased serum concentrations of amiodarone and its pharmacologic effects.

MANAGEMENT: Caution and close clinical monitoring are recommended if amiodarone is prescribed with macrolides. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope.

MONITOR CLOSELY: Methadone may cause dose-related prolongation of the QT interval. Coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. High dosages of methadone alone have been associated with QT interval prolongation and torsade de pointes. In a retrospective study of 17 methadone-treated patients who developed torsade de pointes, the mean daily dose was approximately 400 mg (range 65 to 1000 mg) and the mean corrected QT (QTc) interval on presentation was 615 msec. The daily methadone dose correlated positively with the QTc interval. Fourteen patients had at least one predisposing risk factor for arrhythmia (hypokalemia, hypomagnesemia, concomitant use of a medication known to prolong the QT interval or inhibit the metabolism of methadone, and structural heart disease), but these were not predictive of QTc interval. It is not known if any of the patients had congenital long-QT syndrome.

MANAGEMENT: Caution is recommended when methadone is administered concomitantly with drugs that prolong the QT interval, particularly in the setting of chronic pain management or methadone maintenance for opioid dependency where high dosages may be employed, or if administered to patients with underlying risk factors. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope. If taking drugs that also cause central nervous system and/or hypotensive effects (e.g., psychotropic drugs like tricyclic antidepressants, phenothiazines, and neuroleptics), patients should be made aware of the possibility of additive effects with methadone and counseled to avoid activities requiring mental alertness until they know how these agents affect them.

MONITOR: Coadministration of sirolimus or tacrolimus with other drugs that are also metabolized by CYP450 3A4 may result in elevated plasma concentrations of the macrolide immunosuppressant and/or the coadministered drug(s). The mechanism is decreased drug clearance due to competitive inhibition of CYP450 3A4 activity. Although clinical data are lacking, the possibility of prolonged and/or increased pharmacologic effects of the drugs should be considered.

MANAGEMENT: Pharmacologic responses and/or plasma drug levels should be monitored more closely whenever a macrolide immunosuppressant or another substrate of CYP450 3A4 is added to or withdrawn from therapy, and the dosage(s) adjusted as necessary.

MONITOR: Coadministration of temsirolimus with inhibitors of CYP450 3A4 may increase the plasma concentrations of sirolimus, a major active metabolite of temsirolimus and known substrate of CYP450 3A4. According to the product labeling, administration of temsirolimus in combination with the potent CYP450 3A4 inhibitor ketoconazole resulted in a 2.2-fold and 3.1-fold increase in sirolimus peak plasma concentration (Cmax) and systemic exposure (AUC), respectively, compared to administration of temsirolimus alone. No significant effect on the pharmacokinetics of temsirolimus was reported.

MANAGEMENT: Caution is advised if temsirolimus is prescribed in combination with CYP450 3A4 inhibitors. Pharmacologic response to temsirolimus should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy, and the temsirolimus dosage adjusted as necessary. Patients should be advised to contact their physician if they experience increased adverse effects of temsirolimus such as hyperglycemia (e.g., excessive thirst; increased volume and/or frequency of urination), infections, fever, dyspnea, abdominal pain, diarrhea, and bloody stools.

MONITOR: Coadministration with amiodarone may significantly increase the blood concentrations of cyclosporine. The risk of nephro- and neurotoxicity associated with cyclosporine may be increased. The proposed mechanism is amiodarone inhibition of CYP450 3A4, the isoenzyme responsible for the intestinal and hepatic metabolism of cyclosporine. Enhanced cyclosporine oral bioavailability due to inhibition of intestinal P-glycoprotein efflux transporters may also contribute. In one report, eight transplant patients demonstrated a 31% increase in serum cyclosporine levels following the administration of amiodarone for atrial flutter or atrial fibrillation, despite a 44% reduction in the cyclosporine dosage. Increases in serum creatinine were observed. There have also been case reports of transplant patients stabilized on cyclosporine who developed nephrotoxicity and/or elevated blood levels of cyclosporine following the addition of amiodarone. In one case, cyclosporine blood levels increased more than twofold, and in another, cyclosporine clearance decreased by more than 50%. Significant dosage reductions were required. Due to the long half-lives of amiodarone and its pharmacologically active desethyl metabolite, the interaction may be observed for weeks following discontinuation of amiodarone.

MANAGEMENT: Caution is advised if cyclosporine is used in combination with amiodarone. Cyclosporine blood levels and renal function should be checked frequently and the dosage adjusted accordingly, particularly following initiation, discontinuation or change of dosage of amiodarone in patients who are stabilized on their cyclosporine regimen. Patients should be advised to notify their physician if they experience possible signs of cyclosporine toxicity such as nausea, vomiting, diarrhea, abdominal pain, dizziness, fatigue, headache, tremors, and convulsions.

MONITOR: Coadministration with atazanavir may increase the plasma concentrations of amiodarone, systemic lidocaine, and quinidine. The proposed mechanism is atazanavir inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of these antiarrhythmic agents. The interaction has not been studied but could conceivably lead to serious and/or life-threatening reactions including cardiac arrhythmias and other toxicities.

MANAGEMENT: Caution is advised if atazanavir must be used with amiodarone, systemic lidocaine, or quinidine. Pharmacologic response and plasma antiarrhythmic drug levels should be monitored more closely whenever atazanavir is added to or withdrawn from therapy, and the antiarrhythmic dosage adjusted as necessary.

MONITOR: Coadministration with bosentan may decrease the plasma concentrations of drugs that are substrate-inhibitors of the CYP450 2C9 and/or 3A4 isoenzymes. Conversely, the plasma levels of bosentan may increase. Bosentan is a substrate as well as inducer of CYP450 2C9 and 3A4, thus a mutual interaction may occur with drugs that are substrates as well as inhibitors of these isoenzymes. According to bosentan product labeling, ketoconazole (a potent CYP450 3A4 inhibitor) alone increased the plasma concentrations of bosentan (125 mg orally twice a day) by approximately 2-fold. It is conceivable that concomitant administration of both a CYP450 2C9 inhibitor and a CYP450 3A4 inhibitor may lead to even larger increases in plasma concentrations of bosentan.

MANAGEMENT: When drugs that are known substrate-inhibitors of CYP450 2C9 and/or 3A4 are coadministered with bosentan, the possibility of a diminished therapeutic response to those drugs should be considered. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs, particularly those with a narrow therapeutic range, whenever bosentan is added to or withdrawn from therapy. The possibility of prolonged and/or increased pharmacologic effects of bosentan, including serious adverse effects such as hepatotoxicity, should also be considered. Patients should be advised to notify their physician if they experience signs and symptoms of hepatotoxicity such as fever, rash, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, and jaundice. Concomitant administration of both a potent CYP450 2C9 inhibitor (e.g., fluconazole, amiodarone) and a potent CYP450 3A4 inhibitor (e.g., ketoconazole, itraconazole, ritonavir) is not recommended. Concomitant administration with combination 2C9/3A4 inhibitors (e.g., delavirdine, imatinib, miconazole, voriconazole) should probably be avoided also, if possible.

MONITOR: Coadministration with darunavir may increase the plasma concentrations of amiodarone, bepridil, systemic lidocaine, and quinidine. The proposed mechanism is darunavir inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of these antiarrhythmic agents. The interaction has not been studied but could conceivably lead to serious and/or life-threatening reactions including cardiac arrhythmias and other toxicities.

MANAGEMENT: Caution is advised if darunavir must be used with amiodarone, bepridil, systemic lidocaine, or quinidine. Pharmacologic response and plasma antiarrhythmic drug levels should be monitored more closely whenever darunavir is added to or withdrawn from therapy, and the antiarrhythmic dosage adjusted as necessary.

MONITOR: Coadministration with drugs that are inhibitors of CYP450 1A2 may increase the plasma concentrations of ropinirole, which is metabolized by the isoenzyme. Ciprofloxacin (500 mg twice a day), a known inhibitor of CYP450 1A2, has been reported to increase the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of ropinirole (2 mg three times a day) by an average of 60% and 84%, respectively, in 12 study subjects. The possibility of prolonged and/or increased pharmacologic effects of ropinirole should be considered.

MANAGEMENT: Pharmacologic response to ropinirole should be monitored more closely whenever a CYP450 1A2 inhibitor is added to or withdrawn from therapy, and the ropinirole dosage adjusted as necessary. Patients should be advised to contact their physician if they experience excessive adverse effects of ropinirole such as agitation, hallucinations, orthostasis, sedation, confusion, or increased dyskinesia, flushing, dry mouth, sweating, and heart rate.

MONITOR: Coadministration with drugs that are inhibitors of CYP450 2C9 and/or 3A4 may increase the plasma concentrations of valdecoxib, which is metabolized by these isoenzymes. According to the product labeling for valdecoxib, multi-dose administration of fluconazole (CYP450 2C9/3A4 inhibitor) and ketoconazole (CYP450 3A4 inhibitor) increased the area under the plasma concentration-time curve (AUC) of a single 20 mg dose of valdecoxib by 62% and 38%, respectively. Parecoxib, a prodrug of valdecoxib, may be similarly affected.

MANAGEMENT: The possibility of prolonged and/or increased pharmacologic effects of valdecoxib or parecoxib, including serious adverse effects such as gastrointestinal ulceration and bleeding, should be considered during concomitant therapy with CYP450 2C9 or 3A4 inhibitors, particularly combination (2C9/3A4) inhibitors such as fluconazole, fluvoxamine, imatinib, and zafirlukast. Dose reductions of the COX-2 inhibitor may be required.

MONITOR: Coadministration with drugs that are inhibitors of CYP450 2D6 and/or 3A4 may increase the plasma concentrations of aripiprazole, which is metabolized by these isoenzymes. According to the manufacturer, ketoconazole (200 mg/day for 14 days), a potent CYP450 3A4 inhibitor, increased the area under the plasma concentration-time curve (AUC) of aripiprazole (15 mg single dose) and its active metabolite, dehydro-aripiprazole, by 63% and 77%, respectively. Quinidine (166 mg/day for 13 days), a potent CYP450 2D6 inhibitor, increased the AUC of aripiprazole (10 mg single dose) by 112% but decreased the AUC of dehydro-aripiprazole by 35%.

MANAGEMENT: Pharmacologic response to aripiprazole should be monitored more closely whenever a CYP450 2D6 and/or 3A4 inhibitor is added to or withdrawn from therapy, and the aripiprazole dosage adjusted as necessary. The manufacturer recommends that aripiprazole dosage be reduced to one-half the normal dosage during concomitant administration with ketoconazole or quinidine, and additional dosage adjustments be based on clinical evaluation. No dosage recommendations are available for concomitant administration with less potent CYP450 2D6 or 3A4 inhibitors.

MONITOR: Coadministration with drugs that are inhibitors of CYP450 2D6 may increase the plasma concentrations of atomoxetine, which is primarily metabolized by the isoenzyme. In patients who are extensive metabolizers of CYP450 2D6 (approximately 93% of Caucasians and more than 98% of Asians and individuals of African descent), potent inhibitors of the isoenzyme such as fluoxetine and paroxetine have been shown to increase atomoxetine systemic exposure (AUC) by 6- to 8-fold and peak plasma concentration (Cmax) by 3- to 4-fold. These higher concentrations are similar to those observed in CYP450 2D6 poor metabolizers given the drug alone. In vitro studies suggest that coadministration of CYP450 2D6 inhibitors to poor metabolizers will not further increase atomoxetine plasma concentrations.

MANAGEMENT: Pharmacologic response to atomoxetine should be monitored more closely whenever a CYP450 2D6 inhibitor is added to or withdrawn from therapy, as dosage adjustment of atomoxetine may be necessary in extensive metabolizers. During coadministration, patients should be advised to contact their physician if they experience excessive adverse effects of atomoxetine such as dizziness, dry mouth, anorexia, sleep disturbances, and palpitations.

MONITOR: Coadministration with drugs that are inhibitors of CYP450 2D6 may increase the plasma concentrations of duloxetine, which is partially metabolized by the isoenzyme. The interaction is expected to occur in patients who are CYP450 2D6 extensive metabolizers (approximately 93% of Caucasians and greater than 98% of Asians and individuals of African descent).

MANAGEMENT: The possibility of prolonged and/or increased pharmacologic effects of duloxetine should be considered during concomitant therapy with CYP450 2D6 inhibitors, particularly potent inhibitors such as quinidine, paroxetine, and fluoxetine.

MONITOR: Coadministration with drugs that are inhibitors of CYP450 2D6 may increase the plasma concentrations of galantamine, which is primarily metabolized by the isoenzyme. In multiple-dose pharmacokinetic studies, a potent inhibitor such as paroxetine has been shown to increase the area under the plasma concentration-time curve (AUC) of galantamine by 40%. Data from a population pharmacokinetic analysis of 852 patients demonstrated that amitriptyline, fluoxetine, fluvoxamine, and quinidine decreased the clearance of galantamine by about 25% to 33%.

MANAGEMENT: During concomitant therapy with drugs that inhibit CYP450 2D6 activity, the possibility of prolonged and/or increased pharmacologic effects of galantamine should be considered. Patients should be advised to notify their physician if they experience nausea, vomiting, sweating, weakness, salivation, or slower respirations.

MONITOR: Coadministration with drugs that are inhibitors of CYP450 3A4 may increase the plasma concentrations of aprepitant, which is primarily metabolized by the isoenzyme. According to the manufacturer, coadministration of the potent CYP450 3A4 inhibitor ketoconazole (400 mg/day for 10 days) and a single 125 mg dose of aprepitant on day 5 resulted in a 5-fold increase in the area under the plasma concentration-time curve (AUC) and a 3-fold increase in the mean terminal half-life of aprepitant. In patients with mild to moderate hypertension, coadministration of the moderate inhibitor diltiazem (120 mg three times a day for 5 days) and aprepitant (approximately 230 mg once a day) resulted in a 2-fold increase in the AUC of aprepitant and a 1.7-fold increase in that of diltiazem. No clinically significant changes in ECG, heart rate, or blood pressure were observed beyond those induced by diltiazem alone.

MANAGEMENT: Caution is advised if aprepitant is used with CYP450 3A4 inhibitors, particularly potent ones like protease inhibitors, macrolide antibiotics, itraconazole, ketoconazole, and nefazodone. Pharmacologic response to aprepitant should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy. In addition, many CYP450 3A4 inhibitors are also substrates of the isoenzyme, thus pharmacologic response to these agents should also be monitored during coadministration with aprepitant.

MONITOR: Coadministration with drugs that are inhibitors of CYP450 3A4 may increase the plasma concentrations of repaglinide, which is metabolized by the isoenzyme in the intestine and liver. In nine healthy volunteers, pretreatment with the CYP450 3A4 inhibitor clarithromycin (250 mg orally twice a day for 4 days) increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of repaglinide (0.25 mg single oral dose) by 66% and 41%, respectively, compared to placebo. Increases in repaglinide Cmax and AUC values were observed in every subject. Clarithromycin also increased the mean elimination half-life of repaglinide by 21% (from 1.4 to 1.7 hours), as well as the mean incremental AUC from 0 to 3 hours of serum insulin by 51% and the maximum increase in the serum insulin concentration by 61%. No statistically significant differences were found in the blood glucose concentrations between the clarithromycin and placebo phases, and no subject developed symptomatic hypoglycemia as a result of the interaction. However, the lack of clinical adverse effects may be explained, at least partially, by frequent carbohydrate intake during the study and the use of a subtherapeutic dose of repaglinide.

MANAGEMENT: Because the antidiabetic effect of repaglinide is dose- and concentration-dependent, pharmacologic response to repaglinide should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy. Patients should be advised to regularly monitor their blood sugar and counseled on how to recognize and treat hypoglycemia, which may include symptoms such as headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, and palpitations. The repaglinide dosage may require adjustment if an interaction is suspected.

MONITOR: Coadministration with drugs that are inhibitors of CYP450 3A4 may increase the plasma concentrations of sildenafil, which is primarily metabolized by the isoenzyme. The possibility of prolonged and/or increased pharmacologic effects of sildenafil should be considered.

MANAGEMENT: Caution is advised if sildenafil is coadministered with CYP450 3A4 inhibitors. Dosage adjustments may be appropriate for sildenafil whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy based on efficacy and side effects. Patients should be advised to promptly notify their physician if they experience pain or tightness in the chest or jaw, irregular heartbeat, nausea, shortness of breath, visual disturbances, syncope, or prolonged erection (greater than 4 hours).

MONITOR: Coadministration with drugs that are inhibitors of CYP450 3A4 may increase the plasma concentrations of tadalafil, which is primarily metabolized by the isoenzyme. The possibility of prolonged and/or increased pharmacologic effects of tadalafil should be considered.

MANAGEMENT: Caution is advised if tadalafil is prescribed with CYP450 3A4 inhibitors. Dosage adjustments may be appropriate for tadalafil whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy based on efficacy and side effects. Tadalafil labeling recommends that the dosage not exceed 10 mg once every 72 hours in patients treated concomitantly with a potent CYP450 3A4 inhibitor, such as erythromycin, itraconazole, ketoconazole, protease inhibitors, and nefazodone. Patients should be advised to promptly notify their physician if they experience potential symptoms of PDE5 inhibitor toxicity such as pain or tightness in the chest or jaw, irregular heartbeat, nausea, shortness of breath, visual disturbances, syncope, or prolonged erection (greater than 4 hours).

MONITOR: Coadministration with fluvoxamine may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to competitive inhibition of CYP450 3A4 activity by fluvoxamine.

MANAGEMENT: Caution is advised if fluvoxamine must be used concomitantly with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever fluvoxamine is added to or withdrawn from therapy.

MONITOR: Coadministration with imatinib may increase the plasma concentrations of drugs that are substrates of CYP450 2C9, 2D6 and/or 3A4. The mechanism is decreased clearance due to inhibition of these isoenzymes by imatinib. According to the manufacturer, imatinib increased the mean peak plasma concentration and area under the concentration-time curve of simvastatin (a CYP450 3A4 substrate) by 2- and 3.5-fold, respectively. Data for other substrates are not currently available, although human liver microsome studies indicate that imatinib is a potent competitive inhibitor of all three isoenzymes.

MANAGEMENT: Caution is advised if imatinib must be used concomitantly with medications that undergo metabolism by CYP450 2C9, 2D6 and/or 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever imatinib is added to or withdrawn from therapy.

MONITOR: Coadministration with inhibitors of CYP450 2D6 and/or 3A4 may increase the plasma concentrations of darifenacin, which is a substrate of these isoenzymes. According to the product labeling, coadministration of darifenacin (30 mg once daily) with the mixed CYP450 inhibitor cimetidine resulted in a 42% increase in the mean darifenacin steady-state peak plasma concentration (Cmax) and a 34% increase in the systemic exposure (AUC) compared to administration of darifenacin alone. The potent CYP450 2D6 inhibitor paroxetine (20 mg) increased steady-state AUC of darifenacin (30 mg once daily) by 33%. Erythromycin, a CYP450 3A4 inhibitor, increased the mean steady-state Cmax and AUC of darifenacin (30 mg once daily) by 128% and 95%, respectively. Fluconazole, another 3A4 inhibitor, increased these values by 88% and 84%, respectively.

MANAGEMENT: Pharmacologic response to darifenacin should be monitored more closely whenever a CYP450 2D6 and/or 3A4 inhibitor is added to or withdrawn from therapy, and the darifenacin dosage adjusted if necessary. Patients should be advised to contact their physician if they experience undue adverse effects of darifenacin such as severe abdominal pain or constipation for 3 or more days.

MONITOR: Coadministration with inhibitors of CYP450 3A4 and/or 2C19 may increase the plasma concentrations of cilostazol and or its pharmacologically active metabolites, which are substrates of these isoenzymes. The possibility of prolonged and/or increased pharmacologic effects of cilostazol should be considered. In pharmacokinetic studies, pretreatment with a 400 mg priming dose of ketoconazole (a potent CYP450 3A4 inhibitor) one day prior to coadministration of single doses of ketoconazole 400 mg and cilostazol 100 mg resulted in a 94% increase in cilostazol peak plasma concentration (Cmax) and a 117% increase in cilostazol systemic exposure (AUC). Coadministration of the less potent inhibitor erythromycin (500 mg every 8 hours) with a single 100 mg dose of cilostazol resulted in a 47% and 73% increase in cilostazol Cmax and AUC, respectively, while AUC of 4-trans-hydroxy-cilostazol (an active metabolite with 1/5 the pharmacologic activity) increased by 141% as a result of the inhibition of cilostazol metabolism via CYP450 3A4. Coadministration with 180 mg of diltiazem, a moderate CYP450 3A4 inhibitor, decreased cilostazol clearance by 30% and increased its Cmax by 30% and AUC by 40%. In contrast, cilostazol metabolism was not significantly affected when coadministered with omeprazole, a potent CYP450 2C19 inhibitor, but the systemic exposure to 3,4-dehydro-cilostazol (the most active metabolite of cilostazol) was increased by 69%.

MANAGEMENT: Close clinical and laboratory monitoring is advised whenever a CYP450 3A4 and/or 2C19 inhibitor is added to or withdrawn from cilostazol therapy, and the dosage adjusted as necessary. Patients should be advised to contact their physician if they experience adverse effects of cilostazol such as headache, dizziness, nausea, diarrhea, or irregular heartbeat. The manufacturer recommends a 50% dosage reduction of cilostazol (i.e., 50 mg twice a day) in patients receiving the CYP450 3A4 inhibitors ketoconazole, itraconazole, erythromycin, and diltiazem, or the 2C19 inhibitor omeprazole. A similar dosage adjustment should be considered in patients who develop undue adverse effects during coadministration of cilostazol with other 3A4 and/or 2C19 inhibitors.

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations and pharmacologic effects of aliskiren, which is primarily metabolized by the isoenzyme. According to the product labeling, plasma levels of aliskiren were increased approximately 80% by the potent CYP450 3A4 inhibitor ketoconazole at a dosage of 200 mg twice daily. A 400 mg once daily dose of ketoconazole was not studied but would be expected to further increase aliskiren blood levels.

MANAGEMENT: Pharmacologic response to aliskiren should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy, and the aliskiren dosage adjusted if necessary. Patients should be advised to notify their physician if they experience excessive adverse effects of aliskiren such as dizziness, lightheadedness, diarrhea, abdominal pain, and gastroesophageal reflux.

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations and systemic effects of budesonide, which is metabolized by the isoenzyme. According to budesonide labeling, potent inhibitors can increase the plasma levels of budesonide several fold. For example, an eight-fold increase in the systemic exposure (AUC) has been observed during coadministration of oral budesonide with ketoconazole. In a prospective study of a cystic fibrosis center patient population, 11 of 25 patients receiving high-dose itraconazole (400 to 600 mg/day) and budesonide inhalation therapy (800 to 1600 mcg/day) were found to have adrenal insufficiency (one developed Cushing's syndrome), compared to none in a group of 12 patients treated with itraconazole alone and none in a group of 30 cystic fibrosis patients retrospectively included as controls, 24 of whom had been treated with high-dose inhaled budesonide for several years. Adrenal function improved but did not normalize in 10 of the 11 patients during a follow-up of two to ten months after discontinuation of itraconazole and institution of hydrocortisone replacement therapy.

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of gefitinib, which is primarily metabolized by the isoenzyme. According to the product labeling, administration of gefitinib (250 mg single dose) with the potent inhibitor itraconazole (200 mg once a day for 12 days) increased the mean gefitinib systemic exposure (AUC) by 88% in healthy male volunteers. This increase may be clinically significant, as adverse events of gefitinib are related to dose and exposure.

MANAGEMENT: Caution is advised if gefitinib is administered with CYP450 3A4 inhibitors, particularly potent ones like itraconazole, ketoconazole, nefazodone, delavirdine, ketolide and certain macrolide antibiotics, and most protease inhibitors. Pharmacologic response to gefitinib should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy, and the dosage adjusted as necessary. Patients should be advised to contact their doctor if they experience possible symptoms of gefitinib toxicity such as severe diarrhea, nausea, dyspnea, cough, and fever.

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of solifenacin, which has been shown to be a substrate of the isoenzyme in vitro. According to product labeling, coadministration of solifenacin (10 mg) with the potent CYP450 3A4 inhibitor ketoconazole (400 mg) increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of solifenacin by 1.5- and 2.7-fold, respectively, compared to administration of solifenacin alone.

MANAGEMENT: Pharmacologic response to solifenacin should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy, and the solifenacin dosage adjusted if necessary. Patients should be advised to contact their physician if they experience undue adverse effects of solifenacin such as severe abdominal pain or constipation for 3 or more days.

MONITOR: Coadministration with inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of eletriptan, which is primarily metabolized by the isoenzyme. According to the product labeling, eletriptan peak plasma concentration (Cmax) and systemic exposure (AUC) increased by nearly 3-fold and 6-fold, respectively, during coadministration with the potent inhibitor ketoconazole (400 mg). Likewise, erythromycin (1000 mg) increased eletriptan Cmax by 2-fold and AUC by nearly 4-fold. The half-life of eletriptan increased from about 5 hours to 8 hours with ketoconazole and 7 hours with erythromycin. Verapamil (480 mg), a moderate CYP450 3A4 inhibitor, increased eletriptan Cmax by 2.2-fold and AUC by 2.7-fold, while fluconazole (100 mg), a relatively weak inhibitor, increased eletriptan Cmax by 1.4-fold and AUC by 2-fold. Clinically, this interaction may result in increased risk of vasospastic reactions associated with the use of 5-HT1 receptor agonists, such as coronary artery vasospasm, peripheral vascular ischemia, and colonic ischemia.

MANAGEMENT: Eletriptan should not be used within at least 72 hours of treatment with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, nefazodone, delavirdine, most protease inhibitors, and ketolide and certain macrolide antibiotics. The manufacturer makes no specific recommendations for use with less potent inhibitors, but caution is appropriate. Patients should have vital signs monitored regularly and advised to notify their physician if they experience signs and symptoms of vasospasm such as numbness, tingling, or cyanosis in the extremities; muscle pains; weakness; or chest pain or tightness. Alternatively, other 5-HT1 receptor agonists that are not metabolized by CYP450 3A4 may be considered, such as frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan.

MONITOR: Coadministration with nefazodone may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by nefazodone.

MANAGEMENT: Caution is advised if nefazodone must be used concomitantly with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. A lower initial dosage, as well as clinical and laboratory monitoring, may be appropriate for some drugs.

MONITOR: Coadministration with potent inhibitors of CYP450 3A4 and/or 2C9 may increase the plasma concentrations and pharmacologic effects of ramelteon, which is partially metabolized by these isoenzymes. In healthy volunteers, pretreatment with the potent CYP450 3A4 inhibitor ketoconazole (200 mg orally twice daily for 4 days) increased the peak plasma concentration (Cmax) and systemic exposure (AUC) of ramelteon (16 mg single oral dose on day 4) by 36% and 84%, respectively, compared to administration of ramelteon alone. Likewise, coadministration with fluconazole, a potent CYP450 2C9 inhibitor, resulted in an increase of approximately 150% in the Cmax and AUC of ramelteon following a single 16 mg oral dose. Similar pharmacokinetic changes were also observed with its biologically active metabolite, known as M-II.

MONITOR: Coadministration with saquinavir may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by saquinavir.

MANAGEMENT: Caution is advised if saquinavir must be used concomitantly with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever saquinavir is added to or withdrawn from therapy.

MONITOR: Coadministration with troglitazone may decrease the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is accelerated clearance due to induction of CYP450 3A4 activity by troglitazone.

MANAGEMENT: Caution is advised if troglitazone must be used concomitantly with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever troglitazone is added to or withdrawn from therapy.

MONITOR: Drugs that are inhibitors of CYP450 2D6 may interfere with the analgesic effect of codeine. The mechanism is decreased in vivo conversion of codeine to morphine, a metabolic reaction mediated by CYP450 2D6.

MANAGEMENT: The possibility of reduced or inadequate pain relief should be considered in patients receiving codeine with drugs that inhibit CYP450 2D6. An increase in the codeine dosage or a different analgesic agent may be necessary in patients requiring therapy with CYP450 2D6 inhibitors.

MONITOR: One case report suggests that coadministration of amiodarone and cyclophosphamide may result in increased risk of pulmonary toxicity. The exact mechanism of interaction is unknown, although both agents can individually cause pulmonary toxicity such as pulmonary fibrosis and interstitial pneumonitis and may have additive effects on the lungs during coadministration. In the case report, a patient who had been on amiodarone therapy developed biopsy-proven pulmonary toxicity a little over two weeks after receiving a single, high dose of cyclophosphamide (4000 mg/m2). The time frame was much shorter than would have been predicted with cyclophosphamide alone, suggesting an accelerated pathogenic process. The patient had previously tolerated lower doses of cyclophosphamide while receiving treatment with amiodarone.

MANAGEMENT: Caution is advised during coadministration of amiodarone and cyclophosphamide, particularly at high dosages. Patients should be advised to notify their physician if they experience cough, dyspnea, or any new respiratory symptoms.

MONITOR: Plasma concentrations of cevimeline may be increased when administered concurrently with drugs that inhibit CYP450 2D6 liver enzymes. Cholinergic effects may increase.

MANAGEMENT: Clinical monitoring of patient response and tolerance is recommended and dosage adjustments may be indicated. Patients should be advised to notify their physician if they experience excessive symptoms such as nausea, vomiting, diarrhea, sweating, salivation, visual disturbances, headache, or irregular heartbeats.

MONITOR: QT interval prolongation and torsade de pointes have been reported with the coadministration of loratadine and amiodarone. A 73-year-old woman receiving chronic therapy with amiodarone developed syncope and multiple episodes of torsade de pointes following the addition of loratadine. The exact mechanism of interaction is unknown. Although QT interval prolongation and torsade de pointes are known adverse effects of amiodarone, they have not been associated with loratadine. It is possible that loratadine competitively inhibits the metabolism of amiodarone via CYP450 3A4, since both are substrates of the isoenzyme.

MANAGEMENT: Until more information is available, it may be appropriate to monitor QT interval whenever loratadine is coadministered with amiodarone. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope.

MONITOR: QT interval prolongation and torsade de pointes have been reported with the coadministration of metronidazole and amiodarone. A 71-year-old woman developed marked QTc prolongation (625 ms) and torsade de pointes ventricular tachycardia when she received both metronidazole and amiodarone for the treatment of pseudomembranous colitis and paroxysmal atrial fibrillation. The patient recovered following defibrillation and withdrawal of both medications. An interaction was suspected based on the strong temporal relation between administration of the two drugs and development of the arrhythmia. The authors suggest inhibition of CYP450 3A4 metabolism by metronidazole as a possible mechanism of interaction. However, some studies have found no effect of metronidazole on CYP450 3A4 activity.

MANAGEMENT: Until more information is available, it may be appropriate to monitor QT interval on the ECG if amiodarone is used in combination with metronidazole. Patients treated on an outpatient basis should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope.

MONITOR: QT interval prolongation and torsade de pointes have been reported with the coadministration of trazodone and amiodarone. A 72-year-old woman receiving previously well-tolerated, long-term therapy with amiodarone developed polymorphous ventricular tachycardia following the addition of trazodone. The exact mechanism of interaction is unknown. While QT interval prolongation and torsade de pointes are known adverse effects of amiodarone, they have not been associated with the clinical use of trazodone. However, asymptomatic but significant prolongation of the QT interval occurred in a woman who overdosed on 3 grams of trazodone. It is possible that competitive inhibition of CYP450 3A4 metabolism can occur between trazodone and amiodarone, resulting in increased plasma levels of one or both drugs.

MANAGEMENT: Until more information is available, it may be appropriate to monitor QT interval whenever trazodone is coadministered with amiodarone. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope.

MONITOR: Rifamycins may decrease serum concentrations of amiodarone and its metabolite (DEA). The proposed mechanism is induction of CYP450 3A4 hepatic metabolism. This may result in decreased clinical effectiveness of amiodarone.

MANAGEMENT: Monitoring serum amiodarone and DEA levels and patients' clinical status is recommended if rifamycins are added to or deleted from a stable drug regimen that includes amiodarone. Patients should be advised to notify their physician if they experience worsening of their symptoms (e.g., palpitations or irregular heartbeat).

MONITOR: Thalidomide can cause peripheral neuropathy, and concurrent use of other agents that are also associated with this adverse effect can potentiate the risk. Thalidomide alone can cause nerve damage, and peripheral neuropathy is a common, potentially severe side effect that may be irreversible. Peripheral neuropathy generally occurs following chronic use over a period of months, although there have also been reported cases following relatively short-term use. The correlation with cumulative thalidomide dose is unclear.

MANAGEMENT: Caution is advised if thalidomide is used in combination with other neurotoxic agents. All patients treated with thalidomide should be examined at monthly intervals for the first three months of therapy and periodically thereafter to detect early signs of neuropathy such as burning, tingling, pain, or numbness in the hands and feet. Electrophysiological testing may be performed at baseline and every six months during therapy to detect asymptomatic neuropathy. Consideration should be given to immediate discontinuation of thalidomide in patients who develop peripheral neuropathy to limit further damage. Symptoms may improve or return to baseline in some patients upon discontinuation of thalidomide, although the complete time-course of this toxicity has not been fully characterized. If necessary, therapy should generally be reinstituted only after neuropathy returns to baseline status.

MONITOR: The coadministration with drugs that are inhibitors of the CYP450 2C9 enzymatic pathway may increase the plasma concentrations of celecoxib, which is metabolized by CYP450 2C9. The possibility of prolonged and/or increased pharmacologic effects of celecoxib should be considered.

MANAGEMENT: Monitoring for clinical and laboratory evidence of altered effects of celecoxib is recommended. Patients should be advised to notify their physician if they experience abdominal pain, tarry stools, nausea, vomiting, lethargy or drowsiness.

MONITOR: Theoretically, coadministration with drugs that are inhibitors of CYP450 2C8 and/or 3A4 may increase the plasma concentrations of paclitaxel, which is metabolized by these isoenzymes.

MANAGEMENT: Clinicians should recognize the potential for interaction with drugs that inhibit CYP450 2C8 and/or 3A4 and monitor for evidence of dose-related toxicities of paclitaxel during coadministration. Patients should be advised to contact their physician if they develop signs and symptoms of myelosuppression (eg., pallor, dizziness, fatigue, lethargy, easy bruising or bleeding, or signs of infection such as fever, chills, or sore throat) or neuropathy (e.g., visual disturbances and burning, tingling, or numbness in the hands and feet).

MONITOR: Theoretically, coadministration with sorafenib may increase the plasma concentrations of drugs that are substrates of CYP450 2B6 and/or 2C8. Soratinib has been shown in vitro to be an inhibitor of these isoenzymes.

MANAGEMENT: Caution is advised if sorafenib must be used concomitantly with medications that undergo metabolism by CYP450 2B6 and/or 2C8, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever sorafenib is added to or withdrawn from therapy.

MANAGEMENT: The patient's response to photodynamic therapy should be monitored. Patients should be advised to avoid exposure to sunlight or bright indoor light during the period between application of aminolevulinic acid and photoactivation.

MONITOR: There is some concern that quetiapine may have additive adverse cardiovascular effects in combination with other drugs that are known to prolong the QT interval of the electrocardiogram. Data are conflicting. In clinical trials, there was no statistically significant difference between quetiapine and placebo in the proportions of patients experiencing potentially important changes in ECG parameters including QT, QTc, and PR intervals. However, QT prolongation has been reported in quetiapine overdose and with therapeutic use of other atypical antipsychotic agents such as sertindole, ziprasidone, and risperidone. In one case report, torsade de pointes arrhythmia developed in a patient treated with low-dose quetiapine. However, the relationship to quetiapine is uncertain, as there were multiple confounding risk factors such as hypomagnesemia, a history of QT prolongation (possibly prior to initiation of quetiapine), a history of substance abuse, and uncertain medication compliance. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Some clinicians recommend caution when quetiapine is administered concomitantly with drugs that prolong the QT interval, especially to patients with underlying risk factors. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope.

MONITOR: The risk of peripheral neuropathy may be increased during concurrent use of two or more agents that are associated with this adverse effect. In some cases, the neuropathy may progress or become irreversible despite discontinuation of the medications.

MANAGEMENT: Caution is advised during concomitant use of agents with neurotoxic effects. Patients should be monitored closely for symptoms of neuropathy such as burning, tingling, pain, or numbness in the hands and feet. Since the development of peripheral neuropathy may be dose-related for many drugs, the recommended dosages should generally not be exceeded. Consideration should be given to dosage reductions or immediate discontinuation of these medications in patients who develop peripheral neuropathy to limit further damage. If necessary, therapy should generally be reinstituted only after resolution of neuropathy symptoms or return of symptoms to baseline status. In some cases, reduced dosages may be required.

MONITOR: The use of iodine-containing contrast media for coronary angiography in patients treated with certain antiarrhythmics such as amiodarone may result in significant prolongation of the QT interval. These contrast agents can be arrhythmogenic when injected into the coronary arteries and may have additive effects on cardiac repolarization when coadministered with antiarrhythmic agents that prolong the QT interval. In a retrospective study of patients who underwent cardiac catheterization at a German hospital, 21 patients who had been receiving long-term amiodarone therapy exhibited significantly increased QT interval 12 to 24 hours after catheterization compared to 21 age-matched controls who received cardiac catheterization without prior amiodarone or other QT prolonging treatment. In the amiodarone group, the QTc interval (i.e., QT interval corrected for heart rate) increased on average by 10% from 433 ms to 480 ms. QTc prolongation exceeding 500 ms did not occur in any of the amiodarone patients before catheterization but occurred in 6 patients after catheterization. No significant change was observed in the control group.

MANAGEMENT: Caution is advised if iodine-containing contrast media are used for coronary angiography in patients treated with class IA (e.g., disopyramide, quinidine, procainamide) or class III (e.g., amiodarone, dofetilide, ibutilide, sotalol) antiarrhythmic agents. Increased surveillance and ECG monitoring may be appropriate. Patients who receive outpatient angiographies should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of arrhythmia such as dizziness, palpitations, or syncope.

Orlistat may reduce the bioavailability of oral amiodarone and its active metabolite, N-desethylamiodarone. After administration of orlistat 120 mg three times daily for 5 to 13 days and single doses of amiodarone 1200 mg to healthy subjects, the area under the concentration-time curve (AUC) and maximum plasma concentration of amiodarone and its metabolite were decreased by 20 to 25%. The proposed mechanism is alteration of the gastrointestinal lipid phase due to inhibition of dietary fat absorption by orlistat, which may decrease the absorption of highly lipophilic drugs. The clinical significance is unknown. Until more information is available, it is recommended that patients be monitored for altered efficacy of amiodarone when orlistat is added to or discontinued from their regimen.

The coadministration with drugs that are inhibitors of the CYP450 3A4 and/or 2C9 enzymatic pathways may increase the plasma concentrations of montelukast, which is metabolized by both of these isoenzymes. While clinical data are lacking, the possibility of prolonged and/or increased pharmacologic effects of montelukast should be considered. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate whenever a CYP450 3A4 and/or 2C9 inhibitor is added to or withdrawn from therapy.

Use of echinacea beyond 8 weeks may have hepatotoxic effects. The magnitude of echinacea's potential hepatotoxicity is unclear. However, caution is recommended if echinacea is to be taken for long periods of time concomitantly with other potentially hepatotoxic medications.